The present invention relates to an efficient and palladium-catalyzed, regioselective process for the preparation of a wide variety, of multifunctionally substituted aryl-1-alkynes of the formula (I) starting from aryl tosylates and terminal alkynes in the presence of a base, a bidentate ligand and a protic solvent.
Aryl-1-alkynes play an important role as key synthetic intermediates. The ability of the alkyne moiety of intermediates of the formula I to selectively react with various electrophiles or nucleophiles with or without catalytic assistance of acids or bases or transition metal is well known to those skilled in the art. Thus, aryl-1-alkynes are valuable synthetic precursors for a wide variety of other compound classes, like for example indoles, benzofuranes, isochinolines, benzothiophenes, isoquinolines, N-oxide isoquinolines, acetophenones, benzoic acids, aryl-alkenyls, naphthalenes, cinnolines, chromenones and isocoumarins. In addition, aryl-1-alkynes are well known as pharmaceutically active ingredients and several reports document the activity on a variety of biological targets, as well as the fact that several aryl-1-alkynes are in development or are marketed as drugs (P. A. Philip, M. R. Mahoney, C. Allmer, J. Thomas, H. C. Pitot, G. Kim, R. C. Donehower, T. Fitch, J. Picus, C. Erlichman, J. Clin. Oncol. 2006, 19, 3069-3074; S. Veraldi, R. Caputo, A. Pacifico, K. Peris, R. Soda, S. Chimenti, Dermatology 2006, 212(3), 235-237.)
The use of aryl-1-alkynes is of course not limited to the above-mentioned application. For example it is well known that aryl-1-alkynes can be useful in agricultural applications e.g. as herbicides, fungicides, nematicidals, parasiticides, insecticides, acaricides and arthropodicides. In addition they are used as diagnostic agents, liquid crystals and in polymers.
Among the synthetic repertoire for the preparation of aryl-1-alkynes, the transition metal catalyzed formation of the C(sp)-C(sp2) bond between the aryl and the alkyne moiety is by far the most commonly used strategy (J. Tsuji Palladium in Organic Synthesis. Top. Organomet. Chem.; 2005, Vol. 14, Springer Berlin). For this purpose numerous transition metal catalyzed cross-coupling methodologies between an aryl halide or aryl triflate and a organometalic alkyne involving for example a discrete zinc, tin, boron, copper, silicon species have been developed. In contrast to these methods the palladium-catalyzed and optionally copper co-catalyzed cross-coupling of an aryl halide or aryl triflate and a non-metalated terminal alkyne as precursors (“Sonogashira coupling”) has turned out to be one of the most powerful and straightforward methods for the construction of aryl-1-alkynes, since terminal alkynes can be used without prior transformation into a organometalic derivative. Despite the large number of applications of the Sonogashira reaction the coupling partners of the alkyne component are aryl iodides, aryl bromides and more recently also aryl chlorides and aryl triflates.
Recently the use of aryl tosylates was reported by Buchwald et al. (Angew. Chem. Int. Ed. 2003, 42, 5993-5996). However, only three examples with a toluene-4-sulfonic acid 4-cyano-phenyl ester, a toluene-4-sulfonic acid 3-trifluoromethyl-phenyl ester and a 5-(toluene-4-sulfonyloxy)-isophthalic acid dimethylester were disclosed. No process of ortho-substituted aryl tosylates were described. Further the toxic solvent C2H5CN was used and slow addition of the alkyne component over 8 hours to the reaction mixture is required to obtain the reported yields. Therefore, the scope of the reported process involving PdCl2(CH3CN)2 as catalyst, dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine (X-Phos) as a monodentate ligand and Cs2CO3 as base in refluxing C2H5CN seems to be very limited.
It has now been found that the disadvantages mentioned can be avoided by a direct, catalytic, mild, versatile and regioselective synthesis for aryl-1-alkynes of formula I. The object is achieved by starting from aryl tosylates of formula II and terminal alkynes of formula III in the presence of a bidentate ligand, a palladium catalyst, a base and a protic solvent.
The addition of a bidentate ligand and the use of a protic solvent now allow the preparation of a wide variety of substituted aryl-1-alkynes of formula I. Further it is now no more necessary to slowly add the alkyne component of formula III over a long period of time.